TNFRSF11A and TNFSF11 are associated with age at menarche and natural menopause in white women

Objective: Menarche and menopause mark the lower and upper limits of the female reproductive period. The timing of these events influences women's health in later life. The onsets of menarche and menopause have a strong genetic basis. We tested two genes, TNFRSF11A (RANK) and TNFSF11 (RANKL), for their association with age at menarche (AM) and age at natural menopause (ANM). Methods: Nineteen single nucleotide polymorphisms (SNPs) of TNFRSF11A and 12 SNPs of TNFSF11 were genotyped in a random sample of 306 unrelated white women. This sample was analyzed for the association of the SNPs and common haplotypes with AM. Then, a subsample of 211 women with natural menopause was analyzed for the association of both genes with ANM. Smoking, alcohol intake, and duration of lactation were applied as covariates in the association analyses. Results: Three polymorphisms of TNFSF11 were associated with AM: rs2200287 (P = 0.005), rs9525641 (P = 0.039), and rs1054016 (P = 0.047). Two SNPs of this gene, rs346578 and rs9525641, showed an association with ANM (P = 0.007 and P = 0.011, respectively). Two SNPs of TNFRSF11A were associated with AM (rs3826620; P = 0.022) and ANM (rs8086340; P = 0.015). Multiple SNP-SNP and SNP-environment interaction effects on AM and ANM were detected for both genes. One polymorphism of TNFRSF11A, rs4436867, was not directly associated with either trait but indicated significant interactions with four TNFSF11 polymorphisms on ANM. Two other TNFRSF11A polymorphisms, rs4941125 and rs7235803, showed interaction effects with several TNFSF11 polymorphisms on AM. Both genes manifested significant interaction with the duration of breast-feeding in their effect on ANM. Conclusions: The TNFRSF11A and TNFSF11 genes are associated with the onset of AM and ANM in white women.